Acquisition of Temozolomide Chemoresistance in Gliomas Leads to Remodeling of Mitochondrial Electron Transport Chain

Abstract

Temozolomide (TMZ) is an oral alkylating agent used for the treatment of high-grade gliomas. Acquired chemoresistance is a severe limitation to this therapy with more than 90% of recurrent gliomas showing no response to a second cycle of chemotherapy. Efforts to better understand the underlying mechanisms of acquired chemoresistance to TMZ and potential strategies to overcome chemoresistance are, therefore, critically needed. TMZ methylates nuclear DNA and induces cell death; however, the impact on mitochondria DNA (mtDNA) and mitochondrial bioenergetics is not known. Herein, we tested the hypothesis that TMZ-mediated alterations in mtDNA and respiratory function contribute to TMZ-dependent acquired chemoresistance. Using an in vitro model of TMZ-mediated acquired chemoresistance, we report 1) a decrease in mtDNA copy number and the presence of large heteroplasmic mtDNA deletions in TMZ-resistant glioma cells, 2) remodeling of the entire electron transport chain with significant decreases of complexes I and V and increases of complexes II/III and IV, and 3) pharmacologic and genetic manipulation of cytochrome c oxidase, which restores sensitivity to TMZ-dependent apoptosis in resistant glioma cells. Importantly, human primary and recurrent pairs of glioblastoma multiforme (GBM) biopsies as well as primary and TMZ-resistant GBM xenograft lines exhibit similar remodeling of the ETC. Overall these results suggest that TMZ-dependent acquired chemoresistance may be due to a mitochondrial adaptive response to TMZ genotoxic stress with a major contribution from cytochrome c oxidase. Thus, abrogation of this adaptive response may reverse chemoresistance and restore sensitivity to TMZ, providing a strategy for improved therapeutic outcomes in GBM patients.

Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells

“…In particular, high-grade gliomas (HGGs) display mutations in the TCA enzymes isocitrate dehydrogenase IDH1 and IDH2 (5). Notably, gliomas also present mutations in mitochondrial DNA (mtDNA) and alterations of the ETC, but whether these are early or late events in cancer pathogenesis remains to be determined (6)(7)(8)(9)(10)(11)(12)(13)(14). Finally, p53, which has emerged as an important regulator of mitochondrial metabolism and cellular redox control (15)(16)(17), is often found mutated or functionally inactivated in HGG.…”

Metabolic reprogramming of the tumor

“…The tumor suppression of mitochondrial respiration would decrease endogenous ROS generation, as inhibition of H þ -ATP synthase has been shown to delay ROSdependent cell death (Santamaria et al, 2006). Downregulation of this (Shin et al, 2005) and other (Oliva et al, 2010) ETC complexes is indeed correlated with cancer chemoresistance. Finally, it must be mentioned that future directions of anticancer drug development may also include metabolic targets known to be involved in differentiation.…”

Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-κB-dependent pathway downregulating MGMT expression

“…TMZ, an orally administered alkylating agent with relatively low toxicity, exerts the antitumor activity by interfering with DNA replication. Many randomized clinical trials evidenced that TMZ-based chemo-therapy significantly improved quality of life and prolonged survival of GBM patients (5,6). However, TMZ resistance of GBM is a key factor involved in poor responses and dismal prognosis.…”